201113287 六、發明說明： 【發明所屬之技術領域】 本發明係關於合成鴉片劑之改良方法，更明確的說， 其係關於在嗎啉喃生物鹼6-位置之酮基的還原反應。 【先前技術】 納曲醇（naltrexol)已被主張用來治療海洛因成癮。6/3-納 曲醇是納曲酮（naltrexone)的主要代謝產物。我們希望能找到變 成6α-納曲醇的產業利用途徑。類似結構的分子包括 α-去甲基經嗎啡醇（a -noroxymorphonol)和 α ·納布芬（a -nalbuphine)。 此類化合物製法的現有技術係使用硼氫化物將6-酮基 在對應之納曲酮、去甲基羥嗎啡酮（noroxymorphone)或6 -酮基-納布芬上還原，特別是在低溫下。此方法在 US 5,756,745 (Mallinckrodt)中有所描述。這種硼氣化物的還原反應已被發現 很難放大成商業運轉的規模，伴隨著儲存和硼氫化物的使 用會有安全上的考量，並且硼鹽副產物必需自產品中移除 W02006/035195 ( Johnson Matthey)所描述的是：使用鈿碳觸媒使去 甲基羥嗎啡酮進行氫化反應，接著添加硼氫化鈉而轉化成 納布芬。 WO2008/137672(Mallinckrodt)的目標在於：藉由使用釕、鍺或銥 非對稱觸媒並結合氫源和溶劑來避免硼氫化物的使用。典 型的對掌性觸媒爲Noyori觸媒。氫源包括高達100 atm的氣 態氫或者是（較佳爲）如異丙醇或甲酸之類的氫轉移劑。如 201113287 果使用異丙醇，可以加入少量的活化劑，如KOH ,但是較 佳的氫源爲甲酸和三乙胺之5:2混合物。納布芬的產率爲 83%，而6α-納布芬相對於6冷-納布芬的比率爲99:卜 對於這種轉換作用仍需要簡單且便宜的還原方法。 【發明內容】 因此，本發明提供了一種使嗎啡喃生物鹼中的6 -酮基 還原成對應之6-羥基的方法，其包括使用氣態氫在有非均 質相觸媒和溶劑的情況下使6-酮基氫化，以產生6_羥基產 物。 這種還原反應可適用的分子爲去甲基羥嗎啡酮、納曲 酮、6 -酮基-納布芬、一氫嗎啡酮（hydromorphone)、氫可酮 (hydrocodone)、羥可酮（oxycodone)、羥二氫嗎啡酮（oxymorphone)和納 洛酮（naloxone)。 簡而言之，本發明方法可以由第1圖所示之反應流程 圖來表示。 本發明人發現，雖然非均質相觸媒並非不對稱，還原 反應可以是具有立體選擇性的。在一個較佳實施實例中， 6α-羥基立體異構物爲主要產物。更佳的是，所產生6α-羥基之a，‘ β 比例>85:15。舉例來說，所產生6 α -羥基之 a : β 比例爲86:14。還要更佳的是，所產生6α-羥基之 a : β 比例29 0 ·· 1 0。例如，在要求的情況下，所產生6 α -羥基之α : /3比例293··7。還要更佳的是，所產生6 α -羥基 之α : yS比例>94:6。例如，所產生6 α -羥基之α : /3比例 201113287 乏9 5 : 5。在一個特佳的實施實例中，可以得到9 8 : 2的α :召 比例。可以使用傳統的HPLC方法很容易地進行立體異構 物的解析。 還原反應係在有非均質相觸媒存在的情況下進行。非 均質相觸媒較佳爲在固態擔體上的鉑系金屬。非均質相觸 媒更佳係選自由鈀碳、铑碳、鉑碳、銥碳、釕碳及其混合 物所構成之群組。 觸媒的裝料量可達約10莫耳％。在一個實施實例中， 觸媒的裝料量可達約5莫耳％的濃度，在一個較佳實施實例 中’約0.4-1.0莫耳％。觸媒的來源和固態擔體的來源可能 有很多變化’建議觸媒可藉由傳統的試誤法來做最適化的 選擇。 氫的壓力適合在高達約l〇0psi的範圍內，並且適合在 大約40psi左右（2.758巴）。 $口# t物鹼具有一或多個可能在還原反應期間造成負 面影響的取代基’如3-羥基或14-羥基時，可依傳統的方式 予以保護。或者是’如果這些取代基在氫化反應之前已被 保護（例如’在引導6·酮基嗎啡喃生物鹼合成的步驟中）， 可以選擇保護基使得6-酮基的氫化反應及去保護作用得以 同時發生。在本技術領域，已知有適合之保護基能夠承受 氫化反應或是在氫化反應期間被移除（例如，可參閱，”有 機化學的保護基” ’ peter G.M. Wuts 和 Theodora W. Greene，Wiley Blackwell) 201113287 本發明人已確認可以在酸性、中性或是鹼性pH値環境 下進行氫化反應。因此，還原反應較佳是在約0至約13的 pH値範圍內進行。特佳的PH値範圍爲約5至約7。在此情 況下，本發明人已確認可以極小化yS立體異構物的形成， 並且藉由使降解及產量損失減到最低的方式來進一步改善 本方法。 在一個實施實例中，此方法還進一步包括一種酸。這 種酸較佳爲有機酸，如醋酸；或是無酸，如磷酸、正磷酸 或鹽酸。 可以使用任何一種適合的溶劑，例如水性溶劑、極性 溶劑、非質子偶極性溶劑、非極性溶劑或其混合物。在一 個實施實例中，適當的溶劑爲水，並且希望能使用共溶劑 。這種共.溶劑可以是一種極性溶劑，如醇。在此情況下， 醇可以選自由甲醇、乙醇、異丙醇及其混合物所組成之群 組。較佳的醇爲異丙醇（IP A)。異丙醇的量較佳係維持在或 低於.大約50體積％，因爲當異丙醇的量達到約50體積％以 上時，會對轉化率及a:β比例造成負面影響。或者是， 共溶劑可以是一種非極性溶劑，如芳香烴，例如甲苯。在 一個實施實例中，溶劑可以是如環醯胺之類（例如Ν -甲基吡 咯酮）的極性溶劑和醇（例如甲醇、乙醇或異丙醇，較佳爲 甲醇）之混合物。 適合之反應溫度係在20至75 °C的範圍內，較佳是在約 25至約60°C的範圍內，最佳爲約35至50°C。 201113287 6-酮基與其對應的烯醇可維持在一種互變異構的平衡 狀態，並且有數種因素可能影響這種平衡。這些因素包括 進行還原反應時的pH値或溫度、所使用的溶劑或嗎啡喃生 物鹼反應劑的濃度。然而，如果有烯醇互變異構物存在， 其氫化反應將仍然會產生所要的6 -羥基嗎啡喃生物鹼。因 此，本發明包括6·酮基、6-酮基的對應烯醇或是其互變異 構混合物的還原。 經實驗觀察，嗎啡喃生物鹼中的6-酮基之還原反應可 以在大約24小時內完成，更佳的是在大約1小時至約8小 時內完成。 可以使用傳統的技術來分離和純化產物。舉例來說， 一旦完成還原反應，可逐步進行的包括調整pH値以確保生 物鹼成份在溶液中，接著藉由過濾將觸媒移除，然後使濾 液鹼化以沈澱出生物鹼成份，予以冷卻（如有必要）並且接 著進行過濾和沖洗。典型的純化方法可能包含一或多次再 結晶。 如有需要，可以製備6-羥基嗎啡喃生物鹼的酸加成鹽 。在此情況下，可以製備任何一種適合的鹽類，較佳爲藥 用可接受的鹽類。特佳爲鹽酸鹽。對於習於本技術領域者 而言，皆已熟知這些鹽類的製備方法。在一個示範性的方 法中，可以將6-羥基嗎啡喃生物鹼漿液與醇類（例如乙醇） 或醇/水混合物一起加熱，加入酸，接著予以冷卻和過濾， 而使得6 -羥基嗎啡喃生物鹼轉化成它的酸加成鹽。如有需 201113287 要，可以將鹽類接著被選擇性地再結晶。 本發明方法還可以進一步包括在6-酮基還原反應之前 、之後或同時的還原烷化反應。W02006/035195(Johnson Matthey)係 關於嗎啡喃生物鹼的還原烷化反應，其內容倂入本文參照 。在這個例子中，去甲基羥嗎啡酮和去甲基羥嗎啡醇爲有 用的基質’它們可被烷化形成一系列的14-羥基化鴉片衍生 物。 現在將藉由以下非限制性的實施例來描述本發明。 【實施方式】 實施例1 將6-酮基納布芬還原以生成納布芬生物鹸 將6-酮基納布芬（40克，112.8毫莫耳）溶解於含有正磷 酸（1.56毫升）之IPA(200毫升）和水（200毫升）的混合物中。 反應混合物的pH値爲6.49。反應混合物係在有10 %鈿碳觸 媒（2.4克，0.56毫莫耳的Pt)存在及40 psi氫氣及50 °C的條 件下被氫化。7小時之後，以正磷酸（6.2 5毫升）來調整反應 混合物的pH値，並且予以過濾。加入氨溶液（25毫升）’使 得pH値變成8.5-9.0，並且濾出沈澱物，以50%的IPA水 溶液（60毫升）加以沖洗，予以乾燥，而產生39.3 3克（97% 理論値）的納布芬生物鹼，其純度以HPLC測得爲95.6% ° 納布芬生物鹼轉化成鹽酸納布芬 將納布芬生物鹼（33.1克）裝入含有乙醇（79毫升）和水 (20毫升）的燒瓶中，並且將混合物加熱至5CTC。加入濃鹽 201113287 酸（9.1毫升），使得pH値調整在4-4.5的範圍內。使用冰浴 將所得溶液冷卻至<10°C，並且維持約2小時，再予以過濾 。以乙醇：水（10.6毫升：2.6毫升）沖洗鹽酸納布芬固體，並 且在風扇式烘箱中於5 5 °C下進行乾燥，產生了 3 5.27克（89% 理論値）的鹽酸納布芬。 實施例2 將二氫嗎啡酮還原以生成二氫嗎啡（dihydromorphine) 將二氫嗎啡酮（10克）置入Parr氫化燒瓶中，接著裝入 IPA(50毫升）、水（50毫升）及正磷酸（〇_37毫升）。加入10% 的Pt/C觸媒（1.49克），並且在50T：及40psi氫氣的條件下 使混合物氫化1小時，此時HPLC顯示（對照於參考標準物） 混合物中僅包含二氫嗎啡。 實施例3 將去甲基羥嗎啡酮還原以生成去甲基羥嗎啡醇 將去甲基羥嗎啡酮生物鹼（2克）置入含有水（5毫升）和 鹽酸（0_43毫升）的燒瓶中。加入Rh/C觸媒（1莫耳％)，並且 在40 psi的氫氣及35°C的條件下反應氫化7小時。HPLC 的分析結果顯示有9 8 %轉化成去甲基羥嗎啡醇，非鏡像異 構物的α :石比例爲95:5。 實施例4 將納曲酮還原以生成納曲醇 將納曲酮（20_0克）、ΙΡΑ(100毫升）、水（1〇〇毫升）和 HsPO 4(0.6毫升）置入250毫升的反應燒瓶中，並且加熱至 201113287 50°C。加入10%的Pt/C觸媒（1.3克），並且在50°C及40psi 的條件下反應氫化7小時。加入海港石（Harborlite)(0.2克）’ 並且批次過濾，以去除觸媒殘渣。加入氨溶液（2毫升）’使 得p Η値調整成8.0 - 9.0，同時將混合物冷卻至< 1 〇 °C ’予以 過濾，以水（20毫升）沖洗，並且在55 °C下進行乾燥。獲得 了 11.16克（55.5%的產率）的米色固體，以HPLC分析其爲 α -納曲醇。1H NMR(CDC13 δ /ppm) 0.00(4H，m)，0.39(4H，m)， 0.70(2H,m),l.〇〇(2H,m),1.30(2H,m),1.51(6H,m),2.10(4H,m), 2.20(4H,m),2.45(4H,m),3.41(lH,m),4.15(lH,m),4.41(lH,d,J = 6Hz), 4.55(lH,d,J = 6Hz), 6.3 5 (1 H, d, J = 1 OH z), 6.55(lH,d,J = 10Hz)，5.10-5.70 (6H，非常寬的 s)。I3C NMR(CDC15 5 /ppm) 3.86, 4.09， 9.45， 22.89， 23.20， 28.91， 33.46， 43.28， 47.50， 59.65, 62.16, 67.02, 70.13, 90.74, 117.92, 119.2, 125.5, 131.1, 137.7, 145.9 實施例5 將氫可嗣還原以生成二氫可待因（dihydrocodeine) 將氫可酮U〇克）置入Parr氫化燒瓶中，接著裝入水（50 毫升）、IPA(50毫升）及磷酸（0.3毫升）。加入1〇%的Pt/C觸 媒（1_42克）’並且在50°C及40 psi氫氣的條件下使混合物 氫化。5小時之後’觀察到氫氣的吸收已停止，將海港石 (harborlite)添加至粗製反應混合物中，接著予以過濾。hplc 的分析結果顯示：形成的主要產物係關於二氫可待因的參 •10- 201113287 考標準物。 實施例6 將羥可酮還原以生成羥可醇（oxycodol) 將羥可酮（5克）置入Parr氫化燒瓶中，接著裝入水（50 毫升）及鹽酸（0.3毫升）。加入10 %的Rh/C觸媒（1.51克）， 並且在35 °C及40 psi氫氣的條件下使混合物氫化。6小時 之後，觀察到氫氣的吸收已停止，將海港石（harborlite)添加至 粗製反應混合物中，接著予以過瀘。H PLC的分析結果顯示 :形成的主要產物係關於羥可醇的參考標準物。 實施例7 還原烷化及非對稱酮還原反應的Telescope(納曲醇） 將去甲基羥嗎啡酮（10克，34.8毫莫耳）與NMP(30毫升） 、甲醇（70毫升）以及環丙烷羧醛（2.5毫升，38.5毫莫耳）一起 置入氫化燒瓶中。加入5%的Pt/C (0.32克），並且在40 psi 氫氣的條件下使混合物氫化 3小時。加入海港石 (harborlite)(0.2克），並且過濾混合物。在經過過濾的反應溶液 中加入水（100毫升），並且將所得之漿液冷卻至0-5°C。以 過濾的方式移除沈澱物，並且予以儲存，直到與甲苯萃取 物（150毫升）再結合爲止，該萃取物係以甲苯（5x3 0毫升）自 濾液中萃取活性物質而得。接著以水（5x30毫升）來沖洗已 結合的甲苯萃取物並且與先前濾出的固態沈澱物再結合。 接著將醋酸水溶液（80毫升，1.6%)添加到這種甲苯的反應漿 料中，並且加熱至50°C。一旦所有的固體被溶解（10分鐘） 201113287 ，會分開成兩層，並且在之後將水層冷卻至2 0 - 3 0 °C。加入 5%的Pt/C觸媒（2.83克），並且在50°C及40psi的條件下使 混合物氫化2小時。HPLC的分析結果顯示：形成的主要產 物爲α -納曲醇》 實施例8 —鍋式還原烷化及非對稱酮還原反應（納曲醇） 將去甲基羥嗎啡酮（10克，34.8毫莫耳）與ΝΜΡ(30毫升） 、甲醇（70毫升）以及環丙烷羧醛（2.5毫升，38.5毫莫耳）一起 置入氮化燒瓶中。加入5%的Pt/C (0.32克），並且在40 psi 氫氣的條件下使混合物氫化 3小時。加入海港石 (harborlite)(0.2克），並且過濾混合物。在混合物中添加5%的 卩1/(：(2.7克）新鮮裝料，接著在50°(：及40?5丨氫氣的條件下 使其氫化2小時。HPLC的分析結果顯示：反應溶液中含有 α -納曲醇。 實施例9 一鍋式還原烷化及非對稱酮還原反應（納布芬） 將去甲基羥嗎啡酮（2克，6.9毫莫耳）與ΝΜΡ(6毫升）、 甲醇（14毫升）以及環丙烷羧醛（0.67毫升）一起置入氫化燒 瓶中。加入5%的Pt/C (3.15克），並且在40psi氫氣及50t 的條件下使混合物氫化3小時。在反應末期，對照於參考 樣品的HPLC分析結果顯示：形成的主要產物爲α-納布芬 〇 實施例10 -12- 201113287 6-羥基嗎啡喃生物鹼之比例 下表詳列了本發明方法所產生6-羥基嗎啡喃生物鹼之 a : β 比例 °_____, 6·酮基嗎啡 6-羥基嗎啡喃 觸媒 6-經基嗎啡喃生物 喃生物鹼 生物鹼 鹼之α: Θ比例 羥可酮 羥可醇 Rh/C 93:7 6-酮基納布芬 納布芬 Pt/C 95:5 納曲酮 納曲醇 Rh/C 94:6 納曲酮 納曲醇 Pt/C 93:7 去甲基經嗎啡酮 去甲基羥嗎啡醇 Rh/C 95:5 去甲基經嗎啡酮 去甲基羥嗎啡醇 Pt/C 86:15 氫可酮 二氫可待因 Pt/C 98:2 二氫嗎啡酮 二氫嗎啡 Pt/C 98:2 用來測量α : yS比例的HPLC方法如下，並且係以用於 鹽酸納洛酮的歐洲藥典方法爲基礎： 管 柱：Zorbax Eclipse XDB-C8 5 微米 12.5 公分 x4.0 毫米 移動相：製備如下之溶液：將1.17克的辛烷磺酸鈉溶解於 1000毫升的水中，以50% v/v的磷酸溶液調整成 pH 2.0201113287 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to an improved method for synthesizing opiates, and more particularly to a reduction reaction of a ketone group at the 6-position of a morpholino alkaloid. [Prior Art] Naltrexol has been advocated for the treatment of heroin addiction. 6/3-Natradol is the major metabolite of naltrexone. We hope to find an industrial use route that becomes 6α-naltrexol. Molecules of similar structure include a-noroxymorphonol and a-nalbuphine. The prior art for the preparation of such compounds uses borohydride to reduce the 6-keto group on the corresponding naltrexone, noroxymorphone or 6-keto-nabufen, especially at low temperatures. . This method is described in US 5,756,745 (Mallinckrodt). This boron gasification reduction reaction has been found to be difficult to scale up to commercial scale, with safety considerations associated with storage and borohydride use, and boron salt by-products must be removed from the product. WO2006/035195 (John Matthey) describes the use of a ruthenium carbon catalyst to hydrogenate demethyloxymorphone followed by sodium borohydride to convert to naprofene. The goal of WO 2008/137672 (Mallinckrodt) is to avoid the use of borohydrides by using ruthenium, osmium or iridium asymmetric catalysts in combination with hydrogen sources and solvents. The typical palm-like catalyst is Noyori catalyst. The hydrogen source comprises up to 100 atm of gaseous hydrogen or, preferably, a hydrogen transfer agent such as isopropanol or formic acid. For example, if isopropyl alcohol is used, a small amount of an activator such as KOH may be added, but a preferred hydrogen source is a 5:2 mixture of formic acid and triethylamine. The yield of nabfen was 83%, and the ratio of 6α-nabfen to 6 cold-nabfine was 99: For this conversion, a simple and inexpensive reduction method is still required. SUMMARY OF THE INVENTION Accordingly, the present invention provides a method of reducing a 6-keto group in a morphinan alkaloid to a corresponding 6-hydroxy group, which comprises using gaseous hydrogen in the presence of a heterogeneous phase catalyst and a solvent. The 6-keto group is hydrogenated to produce a 6-hydroxy product. Suitable molecules for this reduction are demethyloxymorphone, naltrexone, 6-keto-nabufen, hydromorphone, hydrocodone, oxycodone. , oxymorphone and naloxone. Briefly, the method of the present invention can be represented by the reaction scheme shown in Figure 1. The inventors have found that although the heterogeneous phase catalyst is not asymmetric, the reduction reaction can be stereoselective. In a preferred embodiment, the 6a-hydroxy stereoisomer is the major product. More preferably, a 6α-hydroxy group is produced, ‘β ratio> 85:15. For example, the ratio of a:β produced by 6α-hydroxyl is 86:14. More preferably, the ratio of a:β produced by 6α-hydroxyl is 29 0 ·· 1 0 . For example, if required, the α of the 6 α -hydroxy group is generated: /3 ratio 293··7. Even more preferably, the α of the 6 α -hydroxy group is produced: yS ratio > 94:6. For example, the α of the 6 α -hydroxy group produced is: /3 ratio 201113287 Lack of 9 5 : 5. In a particularly preferred embodiment, a ratio of 9:2 can be obtained. The analysis of stereoisomers can be easily carried out using conventional HPLC methods. The reduction reaction is carried out in the presence of a heterogeneous phase catalyst. The heterogeneous phase catalyst is preferably a platinum group metal on a solid support. More preferably, the heterogeneous phase catalyst is selected from the group consisting of palladium carbon, rhodium carbon, platinum carbon, rhodium carbon, rhodium carbon and mixtures thereof. The amount of catalyst charged can be up to about 10 mol%. In one embodiment, the loading of the catalyst can be up to a concentration of about 5 mole percent, and in a preferred embodiment ' about 0.4-1.0 mole percent. There may be many changes in the source of the catalyst and the source of the solid support. It is suggested that the catalyst can be optimized by traditional trial and error. The pressure of hydrogen is suitably in the range of up to about 10 psi and is suitably around about 40 psi (2.758 bar). The residue can be protected in a conventional manner by having one or more substituents such as 3-hydroxy or 14-hydroxy which may cause a negative influence during the reduction reaction. Or 'if these substituents have been protected prior to the hydrogenation reaction (eg 'in the step of guiding the synthesis of the ketomorphinan alkaloids), the protecting group can be chosen such that the hydrogenation and deprotection of the 6-keto group At the same time. Suitable protecting groups are known in the art to withstand hydrogenation reactions or are removed during hydrogenation reactions (see, for example, "Protective Groups for Organic Chemistry" 'peter GM Wuts and Theodora W. Greene, Wiley Blackwell ) 201113287 The inventors have confirmed that the hydrogenation reaction can be carried out in an acidic, neutral or alkaline pH 値 environment. Therefore, the reduction reaction is preferably carried out at a pH of from about 0 to about 13. A particularly preferred pH range is from about 5 to about 7. In this case, the inventors have confirmed that the formation of the yS stereoisomer can be minimized and the method is further improved by minimizing degradation and yield loss. In one embodiment, the method further comprises an acid. The acid is preferably an organic acid such as acetic acid or an acid free such as phosphoric acid, orthophosphoric acid or hydrochloric acid. Any suitable solvent may be used, such as an aqueous solvent, a polar solvent, an aprotic dipolar solvent, a non-polar solvent or a mixture thereof. In one embodiment, the appropriate solvent is water and it is desirable to be able to use a cosolvent. The co-solvent can be a polar solvent such as an alcohol. In this case, the alcohol may be selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof. A preferred alcohol is isopropanol (IP A). The amount of isopropanol is preferably maintained at or below about 50% by volume because when the amount of isopropanol reaches above about 50% by volume, the conversion and the ratio of a:β are adversely affected. Alternatively, the cosolvent can be a non-polar solvent such as an aromatic hydrocarbon such as toluene. In one embodiment, the solvent may be a mixture of a polar solvent such as cyclodecylamine (e.g., Ν-methylpyrrolidone) and an alcohol (e.g., methanol, ethanol or isopropanol, preferably methanol). Suitable reaction temperatures are in the range of from 20 to 75 ° C, preferably from about 25 to about 60 ° C, most preferably from about 35 to 50 ° C. 201113287 The 6-keto group and its corresponding enol can be maintained in a tautomeric equilibrium state, and several factors may affect this equilibrium. These factors include the pH 値 or temperature at which the reduction reaction is carried out, the solvent used, or the concentration of the morphinan base reactant. However, if an enol tautomer is present, its hydrogenation will still produce the desired 6-hydroxymorphinan alkaloid. Accordingly, the present invention encompasses the reduction of a corresponding ketol of a 6-keto, 6-keto group or a tautomeric mixture thereof. It has been experimentally observed that the reduction of the 6-keto group in the morphinan alkaloid can be completed in about 24 hours, more preferably in about 1 hour to about 8 hours. Conventional techniques can be used to separate and purify the product. For example, once the reduction reaction is completed, the stepwise step includes adjusting the pH to ensure that the alkaloid component is in solution, then removing the catalyst by filtration, and then alkalizing the filtrate to precipitate the alkaloid component and cooling it. (if necessary) and then filter and rinse. Typical purification methods may involve one or more recrystallizations. An acid addition salt of a 6-hydroxymorphinan alkaloid can be prepared if necessary. In this case, any suitable salt, preferably a pharmaceutically acceptable salt, can be prepared. Particularly preferred is the hydrochloride salt. The preparation of these salts is well known to those skilled in the art. In an exemplary method, a 6-hydroxymorphinan alkaloid slurry can be heated with an alcohol (e.g., ethanol) or an alcohol/water mixture, acid added, followed by cooling and filtration, thereby allowing 6-hydroxymorphinan The base is converted to its acid addition salt. If necessary, the salt can then be selectively recrystallized. The process of the present invention may further comprise a reductive alkylation reaction before, after or at the same time as the 6-keto reduction reaction. W02006/035195 (Johnson Matthey) is a reductive alkylation reaction of morphinan alkaloids, the contents of which are incorporated herein by reference. In this example, demethyloxymorphone and demethyloxymorphol are useful matrices' which can be alkylated to form a series of 14-hydroxylated opioid derivatives. The invention will now be described by the following non-limiting examples. [Examples] Example 1 Reduction of 6-keto-Nabubufen to form Nabuffin Bioptera 6-keto-Nabubufen (40 g, 112.8 mmol) was dissolved in orthophosphoric acid (1.56 ml). A mixture of IPA (200 ml) and water (200 ml). The pH of the reaction mixture was 6.49. The reaction mixture was hydrogenated in the presence of 10% ruthenium carbon catalyst (2.4 g, 0.56 mmol of Pt) and 40 psi of hydrogen at 50 °C. After 7 hours, the pH of the reaction mixture was adjusted with orthophosphoric acid (6.25 ml) and filtered. Ammonia solution (25 ml) was added to make the pH 8.5 8.5-9.0, and the precipitate was filtered off, washed with a 50% aqueous solution of IPA (60 ml) and dried to yield 39.3 3 g (97% of theory) Nabfene alkaloids with a purity of 95.6% by HPLC. Nabuffine alkaloids converted to nabfen hydrochloride Nabuffine alkaloids (33.1 g) were charged with ethanol (79 ml) and water (20 ml) In the flask, and the mixture was heated to 5 CTC. Add concentrated salt 201113287 acid (9.1 ml) to adjust pH 在 to a range of 4-4.5. The resulting solution was cooled to <10 °C using an ice bath and maintained for about 2 hours and then filtered. The nabfen hydrochloride solid was washed with ethanol: water (10.6 ml: 2.6 ml) and dried in a fan oven at 55 ° C to yield 3 5.27 g (89% of theory) of ss. Example 2 Reduction of dihydromorphone to form dihydromorphine Dihydromorphone (10 g) was placed in a Parr hydrogenation flask followed by IPA (50 ml), water (50 ml) and orthophosphoric acid. (〇_37 ml). 10% Pt/C catalyst (1.49 g) was added, and the mixture was hydrogenated for 1 hour under 50T: and 40 psi of hydrogen, at which time HPLC showed (cf. reference standard) that the mixture contained only dihydromorphine. Example 3 Reduction of demethyloxymorphone to give demethyloxymorphol A demethyloxymorphone alkaloid (2 g) was placed in a flask containing water (5 ml) and hydrochloric acid (0-43 ml). Rh/C catalyst (1 mol%) was added, and the reaction was hydrogenated under 40 psi of hydrogen at 35 ° C for 7 hours. Analysis by HPLC showed that 98% was converted to demethyl morphinol, and the ratio of α:stone of non-imaged is 95:5. Example 4 Reduction of naltrexone to produce naltrexol naltrexone (20-0 g), hydrazine (100 ml), water (1 ml) and HsPO 4 (0.6 ml) were placed in a 250 ml reaction flask. And heated to 201113287 50 °C. 10% Pt/C catalyst (1.3 g) was added and the reaction was hydrogenated at 50 ° C and 40 psi for 7 hours. Harborlite (0.2 g) was added and batch filtered to remove catalyst residue. A solution of ammonia (2 ml) was added to adjust p Η値 to 8.0 - 9.0, while the mixture was cooled to < 1 〇 ° C ', filtered, rinsed with water (20 ml), and dried at 55 °C. 11.16 g (55.5% yield) of a beige solid was obtained which was analyzed by HPLC as α-naltrexol. 1H NMR (CDC13 δ / ppm) 0.00 (4H, m), 0.39 (4H, m), 0.70 (2H, m), 1. (2H, m), 1.30 (2H, m), 1.51 (6H, m), 2.10 (4H, m), 2.20 (4H, m), 2.45 (4H, m), 3.41 (lH, m), 4.15 (lH, m), 4.41 (lH, d, J = 6 Hz), 4.55 (lH,d,J = 6 Hz), 6.3 5 (1 H, d, J = 1 OH z), 6.55 (lH, d, J = 10 Hz), 5.10-5.70 (6H, very broad s). I3C NMR (CDC15 5 /ppm) 3.86, 4.09, 9.45, 22.89, 23.20, 28.91, 33.46, 43.28, 47.50, 59.65, 62.16, 67.02, 70.13, 90.74, 117.92, 119.2, 125.5, 131.1, 137.7, 145.9 Example 5 Hydrogen oxime was reduced to form dihydrocodeine. Hydrocodone U gram was placed in a Parr hydrogenation flask followed by water (50 mL), IPA (50 mL) and phosphoric acid (0.3 mL). . 1% by weight of Pt/C catalyst (1 - 42 g) was added and the mixture was hydrogenated at 50 ° C and 40 psi of hydrogen. After 5 hours, it was observed that the absorption of hydrogen had stopped, and harborlite was added to the crude reaction mixture, followed by filtration. The analysis of hplc showed that the main product formed was the reference standard for dihydrocodeine. Example 6 Reduction of oxycodone to form oxycodol oxycodone (5 g) was placed in a Parr hydrogenation flask followed by water (50 ml) and hydrochloric acid (0.3 ml). 10% Rh/C catalyst (1.51 g) was added and the mixture was hydrogenated at 35 ° C and 40 psi of hydrogen. After 6 hours, it was observed that the absorption of hydrogen had ceased, and harborlite was added to the crude reaction mixture, followed by hydrazine. The analysis results of H PLC showed that the main product formed was a reference standard for hydroxycohol. Example 7 Telescope (naltrexolol) for reductive alkylation and asymmetric ketone reduction reactions Demethyloxymorphone (10 g, 34.8 mmol) with NMP (30 mL), methanol (70 mL) and cyclopropane Carboxaldehyde (2.5 ml, 38.5 mmol) was placed together in a hydrogenation flask. 5% Pt/C (0.32 g) was added and the mixture was hydrogenated under 40 psi of hydrogen for 3 hours. Harborlite (0.2 g) was added and the mixture was filtered. Water (100 ml) was added to the filtered reaction solution, and the resulting slurry was cooled to 0-5 °C. The precipitate was removed by filtration and stored until it was recombined with toluene extract (150 ml) which was obtained by extracting the active material from the filtrate with toluene (5 x 30 mL). The bound toluene extract was then rinsed with water (5 x 30 ml) and recombined with the previously filtered solid precipitate. An aqueous acetic acid solution (80 ml, 1.6%) was then added to this toluene reaction slurry and heated to 50 °C. Once all solids have been dissolved (10 minutes) 201113287, they will be split into two layers and the aqueous layer will then be cooled to 20-300 °C. 5% Pt/C catalyst (2.83 g) was added, and the mixture was hydrogenated at 50 ° C and 40 psi for 2 hours. The results of HPLC analysis showed that the main product formed was α-naltrexol. Example 8 - Pot reductive alkylation and asymmetric ketone reduction (naltrexol) Demethyl oxymorphone (10 g, 34.8 m) Moor) was placed in a nitriding flask along with hydrazine (30 mL), methanol (70 mL) and cyclopropanecarboxaldehyde (2.5 mL, 38.5 mmol). 5% Pt/C (0.32 g) was added and the mixture was hydrogenated under 40 psi of hydrogen for 3 hours. Harborlite (0.2 g) was added and the mixture was filtered. 5% 卩 1 / (: (2.7 g) fresh charge was added to the mixture, followed by hydrogenation for 2 hours at 50 ° (: and 40 ° 5 Torr of hydrogen). HPLC analysis showed: in the reaction solution Containing α-naltrexol. Example 9 One-pot reductive alkylation and asymmetric ketone reduction (nabufen) Demethyl oxymorphone (2 g, 6.9 mmol) and hydrazine (6 ml), Methanol (14 ml) and cyclopropanecarboxaldehyde (0.67 ml) were placed together in a hydrogenation flask. 5% Pt/C (3.15 g) was added, and the mixture was hydrogenated under 40 psi of hydrogen and 50 t for 3 hours. At the end of the period, the HPLC analysis results against the reference sample showed that the main product formed was α-nabfen oxime. Example 10 -12- 201113287 Ratio of 6-hydroxymorphinan alkaloids The following table details the method produced by the method of the present invention. -hydroxymorphinan alkaloids a : β ratio °_____, 6 · ketomorphine 6-hydroxymorphine catalyst 6 - via morphinan alkaloid alkaloid base alpha: Θ ratio oxycodone hydroxycohol Rh/C 93:7 6-keto-Nabufenabenbufen Pt/C 95:5 naltrexone naltrexol Rh/C 94 :6 naltrexone naltrexol Pt/C 93:7 demethylating morphinone demethyl morpholol Rh/C 95:5 demethylating morphinone demethyl morphinol Pt/C 86:15 Hydrocodone dihydrocodeine Pt/C 98:2 Dihydromorphone dihydromorphine Pt/C 98:2 The HPLC method used to measure the ratio of α: yS is as follows, and is used in Europe for naloxone hydrochloride. Based on the pharmacopoeia method: Column: Zorbax Eclipse XDB-C8 5 micron 12.5 cm x 4.0 mm mobile phase: Prepare the following solution: Dissolve 1.17 g of sodium octane sulfonate in 1000 ml of water at 50% v/ v phosphoric acid solution adjusted to pH 2.0
:A20毫升乙腈、40毫升THF和940毫升上述溶液 :B 170毫升乙腈、40毫升THF和790毫升上述溶液 流 速：1.5毫升/分鐘 溫 度：40°C 201113287 偵測器：U V @ 2 3 0 n m 注射體積：20微升 處理時間：4 5分鐘 線性梯度： 時間（分鐘） A % v / v B% v/v 0 100 0 40 0 100 50 0 100 '55 100 0 65 100 〇 【圖式簡單說明】 第1圖表示本發明方法之反應流程圖。 【主要元件符號說明】 無0 -14-: A 20 ml of acetonitrile, 40 ml of THF and 940 ml of the above solution: B 170 ml of acetonitrile, 40 ml of THF and 790 ml of the above solution Flow rate: 1.5 ml / min Temperature: 40 ° C 201113287 Detector: UV @ 2 3 0 nm Injection Volume: 20 μl Processing time: 4 5 minutes Linear gradient: Time (minutes) A % v / v B% v/v 0 100 0 40 0 100 50 0 100 '55 100 0 65 100 〇 [Simple diagram] Figure 1 is a flow chart showing the reaction of the method of the present invention. [Main component symbol description] No 0 -14-